Enteric coated pharmaceutical composition and method of manufacturing

ABSTRACT

A high drug load enteric coated pharmaceutical composition is provided which includes a core comprised of a medicament which is sensitive to a low pH environment of less than 3, such as ddl, which composition is preferably in the form of beadlets having an enteric coating formed of methacrylic acid copolymer, plasticizer and an additional coat comprising an anti-adherent. The so-called beadlets have excellent resistance to disintegration at pH less than 3 but have excellent drug release properties at pH greater than 4.5. A novel method of making said pharmaceutical composition is also disclosed.

BRIEF DESCRIPTION OF THE INVENTION

[0001] The present invention is directed to an enteric-coatedpharmaceutical composition comprising an acid labile high drug loadmedicament which is sensitive to a low pH environment of less than 3,such as ddl, which composition is also in the form of beadlets ortablets which includes an enteric coating such as Eudragit L-30-D 55 anda plasticizer, but does not require a subcoat; the beadlets also havingan anti-adherent coat. The so-called beadlets have excellent resistanceto disintegration at pH less than 3 but have excellent drug releaseproperties at pH greater than 4.5. A novel method of making saidpharmaceutical composition is also disclosed.

BACKGROUND OF THE INVENTION

[0002] Enteric coatings have been used for many years to arrest therelease of the drug from orally ingestible dosage forms. Depending uponthe composition and/or thickness, the enteric coatings are resistant tostomach acid for required periods of time before they begin todisintegrate and permit slow release of the drug in the lower stomach orupper part of the small intestines. Examples of some enteric coatingsare disclosed in U.S. Pat. No. 5,225,202 which is incorporated byreference fully herein. As set forth in U.S. Pat. No. 5,225,202, someexamples of coating previously employed are beeswax and glycerylmonostearate; beeswax, shellac and cellulose; and cetyl alcohol, masticand shellac, as well as shellac and stearic acid (U.S. Pat. No.2,809,918); polyvinyl acetate and ethyl cellulose (U.S. Pat. No.3,835,221); and neutral copolymer of polymethacrylic acid esters(Eudragit L30D) (F. W. Goodhart et al., Pharm. Tech., pp. 64-71, April1984); copolymers of methacrylic acid and methacrylic acid methylester(Eudragits), or a neutral copolymer of polymethacrylic acid esterscontaining metallic stearates (Mehta et al., U.S. Pat. Nos. 4,728,512and 4,794,001).

[0003] Most enteric coating polymers begin to become soluble at pH 5.5and above, with maximum solubility rates at pHs greater than 6.5.

[0004] Numerous enteric coated and/or extended release pharmaceuticalcompositions and the methods of making these compositions have beendisclosed in the art. Although some of these previously disclosedcompositions are formed into small beadlets or pellets, they oftencomprise numerous extra ingredients in addition to the medicaments, suchas fillers, buffering agents, binders and wetting agents, all of whichadd to the bulk of the composition and reduce the amount of activemedicament which can be contained in the composition. The processes ofpreparing these aforementioned pharmaceutical compositions requiremultiple time consuming steps, including subcoating and outer coatingsteps. Furthermore, many of these pharmaceutical compositions areintended for delivery in the lower GI tract, i.e. in the colon, asopposed to the upper intestines, i.e. the duodenum of the smallintestine.

[0005] U.S. Pat. No. 5,225,202 discloses enteric coated pharmaceuticalcompositions utilizing neutralized hydroxypropyl methylcellulosephthalate polymer (HPMCP) coating. The pharmaceutical compositionsdisclosed comprise an acid labile medicament core, a disintegrant, oneor more buffering agents to provide added gastric protection in additionto the enteric coating, as well as the enteric coating and aplasticizer. The pharmaceutical composition may also include one or morelactose, sugar or starch fillers. According to the invention disclosedin this reference, when the core includes a drug which is incompatiblewith the enteric coating layer, an additional subcoat layer which actsas a physical barrier between the core and outer enteric coating layeris employed to prevent interaction of the acid labile drug and theacidic enteric coat. The HPMCP enteric coating starts its dissolutionprocess at pH 5.0. The process of preparing this pharmaceuticalcomposition requires numerous coating steps to apply the subcoat andthen the enteric coat.

[0006] U.S. Pat. No. 5,026,560 discloses a pharmaceutical compositionand method of making said pharmaceutical composition, wherein thepharmaceutical composition comprises a Nonpareil seed core produced bycoating sucrose with corn starch, spraying the core with an aqueousbinder in a solution of water or ethanol and with a spraying powdercontaining a drug and low substituted hydroxypropylcellulose, followedby the application of an enteric coating.

[0007] U.S. Pat. No. 4,524,060 recites a slow release pharmaceuticalcomposition which provides a sustained release composition for treatinghypertensive patients, and which comprises a mixture of micronizedindoramin or a pharmaceutically acceptable salt thereof, awater-channeling agent, a wetting agent, a disintegrant, the mixturebeing in the form of a non-compressed pellet and having an enteric coator sustained release coat permeable to gastrointestinal juices.

[0008] U.S. Pat. No. 5,536,507 is directed to a pharmaceuticalcomposition having a delayed release coating or enteric coatings whereinthe active agent in the composition is intended for release of apredominant amount of the drug at a point near the inlet to or withinthe large intestine and at a pH of approximately 6.4-7.0.

[0009] Pharmaceutical compositions which include a medicament which isunstable in an acidic environment such as the stomach and which is notadequately buffered, will require an enteric protective coating toprevent release of such medicament prior to reaching the intestines.

[0010] ddl, (also known as didanosine or 2′,3′-dideoxyinosine, andmarketed by Bristol-Myers Squibb Co. under the brand name Videx®), is anacid labile drug which has the formula

[0011] and which has been shown to be effective in the treatment ofpatients with the HIV virus which causes AIDS. The composition andmethod of inhibiting HIV replication with 2′,3′-dideoxyinosine have beenreported. See U.S. Pat. Nos. 4,861,759, 5,254,539 and 5,616,566, whichare incorporated by reference herein. More recently, Videx® has becomewidely used as a component of the new therapeutic cocktails used totreat AIDS. It is also an acid labile medicament sensitive to a low pHenvironment and will degrade in the stomach.

[0012] Videx® is generally available in a variety of oral dosages,including Chewable/Dispersible Buffered Tablets in strengths of 25, 50,100 or 150 mg of didanosine. Each tablet is buffered with calciumcarbonate and magnesium hydroxide. Videx® tablets also containaspartame, sorbitol, microcrystalline cellulose, Polyplasdone®,mandarin-orange flavor, and magnesium stearate. Videx® Buffered Powderfor Oral Solution is supplied for oral administration in single-dosepackets containing 100, 167 or 250 mg of didanosine. Packets of eachproduct strength also contain a citrate-phosphate buffer (composed ofdibasic sodium phosphate, sodium citrate, and citric acid) and sucrose.A Videx® Pediatric Powder for Oral Solution is also available and whichis supplied for oral administration in 4- or 8-ounce glass bottlescontaining 2 or 4 grams of didanosine respectively, and is to be mixedwith commercial antacid before oral ingestion.

[0013] With particular emphasis on the tablets, whether ingested aloneor as part of a combination (“cocktail”) therapy regimen, the currentchewable/dispersible buffered tablets are not conducive from a patientease of use standpoint. Whereas the other products which are a part ofthe AIDS therapeutic cocktail are capsules or tablets and easilyswallowed, the Videx® (referred to herein as “ddl”) Chewable/DispersibleBuffered Tablets must be thoroughly chewed, manually crushed, oruniformly dispersed in water before administration. Because ddl degradesrapidly at acidic pH, ddl, in its chewable/dispersible form and itsbuffered powder for oral solution, contains buffering agents and isadministered with antacids in the pediatric powder form. However, thepresence of the large quantities of antacid components in theformulation can lead to significant GI imbalance as noted by severediarrhea. Many patients also complain about chewing the large ddltablets (dose=2 tablets of 2.1 g each), the taste of the ddl or the timerequired to disperse the tablets and the volume of fluid (4 oz) requiredfor the dose. All these factors, coupled with the fact that othernucleoside analog drugs are marketed in a more convenient dosagepresentation (i.e. capsule or smaller tablets), necessitate thedevelopment of an innovative dosage form of ddl which is easy to swallowand does not cause discomforting side effects.

[0014] The current adult dose of 200 mg twice a day or possibly 400 mgdaily would require very high drug load beads or particles so that the400 mg dose could be encapsulated in a single capsule. A low drug loadformulation would require multiple capsules/dose, which would be lessconvenient from a patient dosing point of view.

[0015] Accordingly, provision of a coating which prevents release of themedicament in the stomach and allows for release of the drug in thesmall intestine thereby eliminating the need for an antacid which maycause GI imbalance upon chronic use. Furthermore, pharmaceuticalcompositions which include a medicament which is unstable in an acidenvironment such as the stomach will require a protective coating toprevent release of such medicament prior to reaching the intestines.

DESCRIPTION OF THE DRAWING

[0016]FIG. 1 is diagrammatic flow chart generally illustrating theprocess for manufacturing the enteric coated pharmaceutical compositionof the present invention.

DESCRIPTION OF THE INVENTION

[0017] In accordance with the present invention, an enteric coated, highdrug load pharmaceutical composition, and a method of making saidpharmaceutical composition, is provided which includes a medicamentwhich may degrade in a low pH environment but which is protected fromdoing so by the enteric coating. The pharmaceutical composition of theinvention, which is advantageously in the form of beadlets, pellets ortablets, includes a core which comprises a medicament which is sensitiveto a low pH environment, such as ddl, and optionally a binder, adisintegrant or swelling agent, and a filler. The core further comprisesan enteric coating surrounding the core which includes a methacrylicacid copolymer and a plasticizer. The pharmaceutical compostion mayfurther comprise an anti-adherent coat.

[0018] The novel enteric coated pharmaceutical of the invention willprovide for protection of the medicament or therapeutically activeagent, such as ddl, at pH's less than 3 (such as found in the stomach)but will permit drug release at a pH of 4.5 or higher (such as found inthe upper intestines).

[0019] Accordingly, the pharmaceutical composition of the invention willusually include drugs which are chemically unstable in acidicenvironments. The pharmaceutical composition of the invention providesexcellent protection in very acidic environments (pH<3) while notdelaying the rapid release in regions of pH greater than 4, whether thisbe the upper intestine or the duodenum.

[0020] Most of the enteric coating materials known in the art are acidicin nature and hence may cause chemical instability when in contact withacid labile ingredients. This is especially true under high temperatureand humid conditions experienced during an aqueous coating process. Tominimize this acid caused instability, a protective coat or subcoat isusually applied between the particles, beadlets, pellets, etc., and theenteric coat. This protective coat physically separates the acid labiledrug from the acidic enteric coat, and hence improves stability of theformulation.

[0021] A process is thus described by which tablets, beadlets, pellets,and/or particles containing acid labile drugs can be successfullyaqueous enteric coated without application of the protective coat orsubcoat. This process involves raising the pH of the enteric coatingsuspension solution by using alkalizing agents. The pH of the coatingsuspension is raised below the point where enteric integrity of thepolymer could be lost. The process may also involve the inclusion ofbinders, such as sodium carboxymethylcellulose, fillers, such asmicrocrystalline cellulose, disintegrants, such as sodium starchglycolate, and other excipients, such as magnesium oxide, which arerelatively alkaline in nature, in the formulations intended for entericcoating. These steps provide a more stable composition for the acidlabile drug in the core. As a result, there is no incompatibility and noneed for a protective subcoat between the acid labile drug and theacidic enteric coat. This process not only eliminates the costlyadditional subcoating step, but allows quicker release of the drug sincethe added subcoat layer delays drug release.

[0022] Normally, drug beads are formed by preparing a wet mass which isextruded into threads or noodles. These are spun on a high-speedrotating plate which breaks these into small pieces and rounds the endsto make spherical particles by a process known as spheronization. Thisspheronization generates centrifugal force. Under these forces, if theparticles do not have enough moisture absorbent, the moisture will beextracted out of the particles (drawn to the surface), which will causeagglomeration. Microcrystalline cellulose is a good moisture absorbentand is thus an excellent spheronization aid. Often more than 15%, andusually more than 30%, is needed to obtain good spheronizationcharacteristics.

[0023] It has been observed that when moisture is drawn to the surfaceduring spheronization, dry powder could be dusted on the particles toquench the moisture and prevent agglomeration. It was believed by theinventors herein that this process could be used to completely eliminatethe use of moisture absorbent in the formulation to prepare high drugload beads. It was further believed by the inventors that the drug withdry binder (if necessary) and optional disintegrant could be blended. Amajor portion of this dry blend could be wet massed, extruded, and theremaining dry blend used for quenching the moisture that surfaces duringspheronization. This technique allows very high drug loads and would notchange the composition of the bead, regardless of the amount of dryblend used for dusting.

[0024] The process of the present invention allows for formation ofbeads with very high drug load (up to 100%), and generally involves thepreparation of a dry blend of powdered drug substance with or without avery small amount of suitable binder and optional disintegrant. The drugitself, the drug/dry binder mixture, or the drug/dry binder/disintegrantmixture should be capable of becoming tacky upon moistening. A majorportion (70-95%) of this blend is wet massed, extruded and spheronizedas is conventionally performed in the art for bead formation. A minorportion (5-30%) of the blend is set aside for dusting. As thespheronization process proceeds, extrudate strands break and theparticles are rounded off. During this process, moisture is extractedout of these particles. The portion of the dry blend set aside earlieris dusted upon the moist particles to quench the surface moisture. Thisrenders the particles relatively dry and free to move in a conventionalrope formation pattern. Accordingly, spheronization of the beadsprogresses without agglomeration.

[0025] Often, enteric-coated or modified release beads or particles areprepared for oral delivery of the drugs in capsule dosage form. Uponoral ingestion the capsule shell dissolves allowing the contents in thecapsule to be exposed to the gastric contents. Due to the presence offluids in the stomach, exposed particles become moistened. If the moistparticles do not stick together, they will disperse into the gastriccontents and may begin to enter the duodenum based on the sizedistribution and other factors which control the gastric transit time.However, if the particles become tacky upon moistening, they may sticktogether as one or more lumps. In this case, such lumps may behave aslarge particles and their gastric emptying time will be variabledepending upon the size and the strength of the lumps formed. In thiscase, such a dosage form would not behave as a true multiparticulatesystem. In order to solve this problem, according to the process of thepresent invention, enteric-coated beadlets, pellets, particles ortablets are coated with a hydrophobic material before encapsulation. Theamount of hydrophobic coating is kept to a level where it is just enoughto prevent particle sticking after the capsule shell has dissolved, butnot too much to retard dissolution. By this simple process, theparticles behave as individual particles, and the gastric transit timeis closer to that which is expected for the particle size for which thedosage form was designed, thus resulting in a more predictable and lessvariable dosage form.

[0026] The process of the present invention illustrates the preparationof high (up to 100%) potency (uncoated) beadlets, for acid labile drugs,such as ddl, using an aqueous process. No specialized equipment isrequired as conventional extrusion and spheronization equipment wasfound to be adequate for beadlet formation. Use of an alkaline binder,such as sodium carboxymethylcellulose, and dusting during spheronizationwith a dry blend mixture comprising the medicament, and optionallybinder and a disintegrant, insured chemical stability of the medicamentand maximized the drug load. The process of the present inventionresulted in high (>90%) yield of beads of narrow particle size cut.

[0027] The invention is particularly adapted to pharmaceuticalcompositions such as beadlets, pellets or tablets, preferably beadlets,containing ddl as the medicament. ddl will be present in an amount ofabout up to 100% of the composition in the coated beadlets.

[0028] The coated beadlets pass through the stomach first. The transittime for the stomach is approximately two hours and the pH of thisregion is approximately 1 to 3. The enteric coating component allows themedicament core to remain substantially intact and thus prevents thepharmacologically active substance from being released in this region orthe acid from penetrating through to the bead core. The beadlets thenpass through the small intestine wherein the majority of the entericcoating component will dissolve and release the pharmacologically activesubstance therein. In normal flow direction therethrough, the smallintestine consists of the duodenum, jejunum and ileum. Transit timethrough the small intestine is approximately 24 hours and the pH ofthese regions is approximately 5 to approximately 7.2.

[0029] As used herein “enteric coating”, is a polymer material ormaterials which encases the medicament core. The polymeric entericcoating material in the present invention does not contain any activecompound, i.e. any therapeutically active agent, of the presentinvention. Preferably, a substantial amount or all of the entericpolymer coating material is dissolved before the medicament ortherapeutically active agent is released from the dosage form, so as toachieve delayed dissolution of the medicament core. A suitablepH-sensitive polymer is one which will dissolve with intestinal juicesat the higher pH levels (pH greater than 4.5), such as within the smallintestine and therefore permit release of the pharmacologically activesubstance in the regions of the small intestine and not in the upperportion of the GI tract, such as the stomach.

[0030] The polymer coating material is selected such that thetherapeutically active agent will be released when the dosage formreaches the small intestine or a region in which the pH is greater thanpH 4.5. Preferred coating pH-sensitive materials, which remain intact inthe lower pH environs of the stomach, but which disintegrate or dissolveat the pH commonly found in the small intestine of the patient. Theenteric polymer coating material begins to dissolve in an aqueoussolution at pH between about 4.5 to about 5.5. The pH-solubilitybehavior of the enteric polymers of the present invention are such thatsignificant dissolution of the enteric polymer coating will not occuruntil the dosage form has emptied from the stomach. The pH of the smallintestine gradually increases from about 4.5 to about 6.5 in theduodenal bulb to about 7.2 in the distal portions of the small intestine(ileum). In order to provide predictable dissolution corresponding tothe small intestine transit time of about 3 hours and permitreproducible release therein, the coating should begin to dissolvewithin the pH range of the duodenum and continue to dissolve at the pHrange within the small intestine. Therefore, the amount of entericpolymer coating should be such that it is substantially dissolved duringthe approximate three hour transit time within the small intestine.

[0031] The pharmaceutical medicament present in the core will be an acidlabile drug such as ddl, pravastatin, erythromycin, digoxin, pancreatin,ddA, ddC, and the like. The present invention is not limited to thesedrugs and other drugs may be used as well.

[0032] One or more binders may be present in the core in an amountwithin the range of from about 0 to about 10% and preferably about 1% byweight of the composition. Sodium carboxymethylcellulose is thepreferred binder most suitable for use herein. Examples of other binderswhich may be used include Avicel™ PH101, Avicel™ RC 591, Avicel™ CL-611,(FMC Corp), Methocel™ E-5 (Dow Corp.), Starch 1500 (Colorcon, Ltd.),Hydroxypropyl Methylcellulose (HPMC) (Shin-Etsu Chemical Co., Ltd.),Polyvinylpyrrolidone, Potassium Alginate and Sodium Alginate.

[0033] The core of the composition of the invention may also include oneor more disintegrants or swelling agents in an amount within the rangefrom about 1% to about 4% by weight of the composition, such as sodiumstarch glycolate marketed under the trademark EXPLOTAB (Edward MendellCo.), Ac-Di-Sol (cross-linked sodium carboxymethylcellulose) (FMC Corp),croscarmellose sodium, corn starch, or cross linkedpolyvinylpyrrolidone.

[0034] The core employed in the pharmaceutical composition of theinvention may be formed of a beadlet or pellet having a diameter of fromabout 0.5 to about 5 mm, and preferably from about 1 to about 2 mm. Thecore will preferably be in the form of a beadlet or a pellet.

[0035] In forming the enteric coated pharmaceutical composition of theinvention, an enteric coating solution of Eudragit L-30-D 55 will beemployed. Eudragit L-30-D 55 is an aqueous acrylic resin dispersion, ananionic copolymer derived from methacrylic acid and ethyl acrylate witha ratio of free carboxyl groups to the ester of approximately 1:1, and amean molecular weight of approximately 250,000, is supplied as anaqueous dispersion containing 30% w/w of dry lacquer substance, and ismarketed by Rohm-Pharma Co., Germany. As an aqueous-based coating, nodangerous or environmentally harmful organic solvents are utilized.

[0036] Although Eudragit is the preferred coating polymer, the inventionis not limited in this respect and other enteric coating polymers knownin the art, such as hydroxypropyl methylcellulose phthalate HP50(HPMCP-HP50) (USP/NF 220824), HP55 (HPMCP-HP55) (USP/NF type 200731) andHP55S available from Shin Etsu Chemical, Coateric™ (polyvinyl acetatephthalate) (Colorcon Ltd.), Sureteric™ (polyvinyl acetate phthalate)(Colorcon, Ltd.), or Aquateric™ (cellulose acetate phthalate) (FMCCorp.) and the like may be employed

[0037] The enteric coating will also preferably contain a plasticizerwhich is preferably diethyl phthalate, although the invention is notlimited in this respect and other plasticizers may be used such astriethyl citrate (Citroflex- 2), triacetin, tributyl sebecate, orpolyethylene glycol. Optionally an anti-adherent (anti-agglomerant)which is advantageously a hydrophobic material such as talc, magnesiumstearate or fumed silica, with talc being preferred, can be appliedafter coating the beadlet or pellet.

[0038] The enteric coating employed is substantially easier to processthan previously reported coating systems, and is especially advantageousfor coating small diameter, low mass particles (beadlets) with minimalprocessing problems (agglomeration) without the need for organicsolvents.

[0039] The above enteric coating will include methacrylic acid copolymerin an amount of approximately 5% -30%, and preferably 10% -20% by weightbased on solids content of the enteric coating solution, and plasticizerin an amount of approximately 1%-6%, and preferably 2%-3% by weight.

[0040] All of the above weights are based on total concentration ofsolids in the enteric coating solution/suspension.

[0041] The enteric coating will thus contain from about 5% to about 35%by weight of solids, and from about 65% to about 95% by weight of water.

[0042] In general, where the core includes a drug which is incompatiblewith the enteric coating layer, a subcoat layer which may be comprisedof one or more film-formers or plasticizers, and which acts as aphysical barrier between the core and the outer enteric coating layerwill be employed. However, unlike previously reported coatings such asthat disclosed in U.S. Pat. No. 5,225,202, the novel pharmaceuticalcomposition of the invention, as a result of the novel process utilizedin making the composition of the present invention and the pH adjustmentof the coating, does not require a subcoat since the need for such aninsulating layer is eliminated by stabilizing the beadlets with analkalizing agent and by aqueous coating at pH 5. Since the coating isdesigned to breakdown at pH 5.5, the enteric coating applied at pH 5permits relatively rapid breakdown in the intestine as only a smallamount of additional alkalinity is required to bring the pH to 5.5.

[0043] The enteric coating will be present in a weight ratio to the coreof within the range of from about 5% to about 30% for release in thesmall intestine, but may be increased to approximately 60% for releasein the colon.

[0044] A preferred enteric coated beadlet formulation is set out below.Possible Preferred Material Range % Composition Total % CORE Drug(didanosine)   50-100.0 95.00 NaCMC   0-10.0  1.00 Na Starch Glycolate  0-10.0  4.00 COATING Eudragit L-30-D 55  5.0-30.0 10-20 DiethylPhthalate 0.5-6.0 1.5-3.0 ANTI-ADHERENT Talc 0.1-4.0 0.2-0.5

[0045] The enteric coated pharmaceutical composition in the form ofbeadlets or pellets may be prepared by a process which comprises thesteps of first preparing uncoated beadlets by preparing a dry blendcomprised of an acid labile medicament, a binder, such as NaCMC, and adisintearant, such as sodium starch glycolate, using a tumbling typeblender, a planetary mixer, or a high shear mixer. A portion in anamount from about 5%-30%, and preferably 10%-20%, of the dried blend isset aside for later dusting during spheronization. Water is then addedto the remaining 70%-95% of dry blend and granulated to a suitable wetgranulation mass using a planetary or high shear mixer. The wet mass isextruded, for example, employing a Nica or other type extruder to forman extrudate which is then placed in a spheronizer such as Caleva, Nicaor other type to form wet beadlets which are dusted duringspheronization with the 5%-30% of dry blend previously set aside. Thebeadlets are then sized through mesh screens to obtain the desiredbeadlet sizes. The beadlets may then be dried by tray drying or by fluidbed drying. The general process of the present invention using ddl asthe acid labile medicament is diagrammatically illustrated in FIG. 1.

[0046] The dried beadlets or pellets may then be coated with an entericfilm coating suspension comprising Eudragit L-30-D and plasticizer(diethyl phthalate), using a fluid bed coater, such as a Wurster spraycoating system or other suitable coating system, and then dried. Duringpreparation of the film coating suspension, a NaOH solution is added tothe suspension until a pH of 5.0±0.1 is obtained. Stabilization of thebeadlets with a binder and the adjustment of the enteric film coatingsuspension to pH 5 eliminates the need for a subcoat or insulatinglayer. The advantage here is that an enteric coating at pH 5 permitsrelatively rapid breakdown in the intestine since only a small amount ofalkalinity is required to bring the pH to 5.5.

[0047] To prevent clumping of the film coated beads, a hydrophobicanti-adherent (talc) is then added to the film coated beads and blended.

[0048] The so-formed beadlets or pellets may then be filled into hardshell capsules, such as gelatin capsules of varying sizes depending onthe dosage of medicament desired.

[0049] The Examples represent preferred embodiments of the presentinvention. The following examples further describe the materials andmethods used in carrying out the invention and are intended to be forillustrative purposes only, and are not intended to limit the scope orspirit of this invention or the claims in any way. All temperatures areexpressed in degrees Centigrade unless otherwise indicated and all meshsizes are U.S. standard ASTM.

EXAMPLE 1

[0050] A ddl formulation in the form of enteric-coated beadlets havingthe following composition was prepared as described below. WEIGHT %WEIGHT % OF OF FINAL COMPOSITION COMPONENT FORMULATION A: PELLET COREddI 95 77.744 Na CMC 1 0.818 Na Starch Glycolate 4 3.273 B: COATINGEudragit L-30-D 55 (dry basis) 87 15.621 Diethyl Phthalate 13 2.343 (pHadjustment to 5.0 ± 0.1) C: ANTI-ADHERENT Talc 100 0.200 D: CAPSULE Size0 clear body and cap

[0051] The preparation of ddl beadlets commenced with the screening andblending of a mixture of ddl, sodium starch glycolate, and sodiumcarboxymethylcellulose. The resulting blend was then screened again andre-blended. Approximately 10%-20% of the second blend was then removedand set aside for dusting during spheronization. The remaining blend wasthen granulated to a suitable wet mass endpoint using a planetary mixeror high shear mixer. Approximately 200-360 g of water per 1 kg of dryblend was added while mixing until a suitable wet mass was achieved forextrusion. The wet mass was extruded through a suitable screen using anextruder (Nica Model E140, Feeder Speed 1, Agitator Speed 1), whichachieved approximately 10/18 mesh fraction beads upon spheronization.The extrudate was transferred to a suitable spheronizer (Caleva Model 15at 500 rpm, or Q-400 Marumerizer™ at 700 rpm), and spheronized at mediumspeed using a medium cross-hatch plate or a radial design plate forapproximately 1-5 minutes. The 10%-20% of the previously prepared dryblend which was set aside was then used to dust the beads to preventagglomeration. After the appropriate spheronization time, the productwas discharged into an appropriate container.

[0052] The spheronized wet beads were then gently passed through #10 and#18 size mesh screens to collect 10/18 mesh product fraction. The over10 and under 18 sized mesh fractions were returned to the extruder forre-extrusion and re-spheronization. This process was continued until atleast 90% of the product fraction was obtained. The 10/18 mesh productfraction was then dried using a hot air tray dryer or a fluid bed typedryer to a predetermined pre-specified moisture content. The dried beadswere screened through #10 and #20 mesh screens to remove any lumps orundersized beads. The 10/20 mesh product fraction dried beads weretransferred to a suitable container lined with two polyethylene bags.The net weight was determined, and the % yield and accountability of thebead manufacturing process was calculated.

[0053] To prepare sufficient quantities of film coating suspension tocoat the bead batch, Eudragit L-30-D 55 was filtered through a #60 meshscreen to remove any lumps present therein. The filtered Eudragit wasweighed and then added with stirring to a tarred vessel containingone-half the amount of water required. The mixture was continuouslystirred for 5 minutes or until a uniform mixture was visually evident.With continuous stirring, diethyl phthalate was added to the vessel andstirring continued for 20 minutes or until a uniform mixture wasvisually evident. A pH meter was then standardized using pH 4 and pH 7buffers. With continued stirring, a NaOH solution was added to thevessel until a pH of 5.0±0.1 was obtained. The formula weight of thecoating suspension was adjusted using water and stirring was continuedfor an additional 10 minutes.

[0054] In the bead coating procedure, a fluid bed processor was set upfor a Wurster spray coating system or other suitable coating system. Theideal parameters for the spray coating system include an AeromaticSTREA-1, 300 g charge, 0.8 mm tip, 8 g/min spray rate, spray pressure1.0 bar, inlet temp. 64° C., outlet temp. 42° C.; Glatt GPCG-5 withWurster column, 1500 g, 1.2 mm tip, 20 g/min spray rate, spray pressure1.0 bar, inlet temp 65° C., product temp. 48° C., outlet temp. 42° C.

[0055] Before commencing application of the film coating suspension, thebeads may optionally be pre-heated to approximately 50° C. forapproximately 5 min. A 16%-20% w/w film coating was applied using thepreviously described coating parameters. After film coating wascompleted the inlet temperature was reduced to maintain a producttemperature of approximately 50° C. and the beads were then dried for25±10 minutes. The net weight of the film coated beads was determined.The percentage of the film coating to the beads was calculated. Theweight of the talc to add based on the net weight of the beads wasdetermined. Actual % gain due to the film coat depends on the efficiencyof the coating operation. The amount of coating applied can be adjustedto achieve the target weight gain due to coating. The determined weightof talc was then weighed out. The film coated beads were placed in asuitable tumbling type blender with the talc and blend for 15±5 minutes.The beads were then transferred to a suitable container(s) lined withtwo polyethylene bags and the net weight was determined.

[0056] The so-formed beadlets may then be filled into capsules orshells, such as gelatin capsules for ease of swallowing.

[0057] The so formed enteric coated ddl product was found to giveexcellent protection against gastric acid (at pH of 3) but had excellentrelease of ddl at pH's above 5.

EXAMPLE 2

[0058] A preferred ddl formulation in the form of enteric coatedbeadlets was prepared as described below. ddl (0.7774 kg), sodium starchglycolate (0.0327 kg) and NaCMC (0.0082 kg) were placed into a suitableblender/mixer. If a tumbling type blender was used, the mixture wasblended for 10±2 min. If a planetary mixer was used, the mixture wasmixed for 10±2 min. If a high shear mixer was used, the mixture wasmixed for 5±2 min. If a tumbling type blender or planetary type mixerwas used, the blend was milled through a Fitzmill equipped with hammersforward, #1 plate, and set at medium speed. This milled material wasthen placed into a tumbling type blender or planetary mixer and blendedfor 10±2 min. Prior to blending, if any of the ingredients requireddelumping, they were passed through a #20 mesh stainless steel screen.

[0059] Approximately 10%-20% of the second blend was then removed andset aside for dusting during spheronization. The remaining blend wasthen granulated to a suitable wet mass endpoint using a planetary mixeror high shear mixer. Approximately 200-360 g of water per 1 kg of dryblend was added while mixing until a suitable wet mass was achieved forextrusion. The wet mass was extruded through a suitable screen using aNica Model E140, Feeder Speed 1, Agitator Speed 1 extruder whichachieved a 10/18 mesh fraction bead upon spheronization. The extrudatewas transferred to a suitable spheronizer, either a Caleva Model 15 at500 rpm, or Q400 Marumerizer™ at 700 rpm, and spheronized at mediumspeed using a medium cross-hatch plate (0.3 mm-0.4 mm) or a radialdesign plate for approximately 1-3 minutes. The 10%-20% of thepreviously prepared dry blend which was set aside was then used to dustthe beads to prevent agglomeration. After the appropriate spheronizationtime, the product was discharged into an appropriate container.

[0060] The spheronized wet beads were then gently passed through #10 and#18 size mesh screens to collect 10/18 mesh product fraction. The over10 and under 18 sized mesh fractions were returned to the extruder forre-extrusion and spheronization. This process was continued until atleast 90% of the product fraction was obtained. The 10/18 mesh productfraction was then dried using a hot air tray dryer or a fluid bed typedryer set at 55° C. to 60° C. (e.g. Glatt GPC-5, Inlet temp. 60° C.,Product temp. 50° C., Outlet temp. 42° C.) to achieve a predeterminedpre-specified moisture content. The dried beads were screened through#10 and #20 mesh screens to remove any lumps or undersized beads. The10/20 mesh product fraction dried beads were transferred to a suitablecontainer lined with two polyethylene bags. The net weight wasdetermined, and the % yield and accountability of the bead manufacturingprocess was calculated.

[0061] To prepare sufficient quantities of film coating to coat 1 kg ofthe bead batch, the solids quantities of Eudragit deposited on 1 kg ofbeads was 0.1562 kg. The quantities of diethyl phthalate deposited on 1kg of beads was 0.0234 kg. The Eudragit L-30-D 55 was filtered through a#60 mesh screen to remove any lumps present therein. The filteredEudragit (0.1562 kg, dry weight) was then added with stirring to atarred vessel containing one-half the amount of water required. Themixture was continuously stirred for 5 minutes or until a uniformmixture was visually evident. With continuous stirring, diethylphthalate (0.0234 kg) was added to the vessel and stirring continued for20 minutes or until a uniform mixture is visually evident. A pH meterwas then standardized using pH 4 and pH 7 buffers. With continuedstirring, a NaOH solution is added to the vessel until a pH of 5.0±0.1is obtained. The formula weight of the coating suspension is adjustedusing water and stirring is continued for an additional 10 minutes.

[0062] The beadlets were then coated using a Wurster spray coatingsystem. Ideal parameters for the spray coating system included anAeromatic STREA-1, 300 g charge, 0.8 mm tip, 8 g/min spray rate, spraypressure 1.4 bar, inlet temp. 64° C., outlet temp. 42° C.; Glatt GPCG-5with Wurster column, 1500 g, 1.2 mm tip, 20 g/min. spray rate, spraypressure 1.0 bar, inlet temp 65° C., product temp. 48° C., outlet temp.42° C.

[0063] Before commencing application of the film coating suspension, thebeads may optionally be pre-heated to approximately 50° C. forapproximately 5 min and dried for 25±10 minutes. A 16%-20% w/w filmcoating using the previously established coating parameters was applied.After film coating is complete the inlet temperature was reduced tomaintain a product temperature of approximately 50° C. and the beadswere then dried for 25±10 minutes. The net weight of the film coatedbeads was determined. The percentage of the film coating to the beadswas calculated.

[0064] The weight of the talc (at 0.2% level) to add based on the netweight of the beads was determined. The determined weight of talc wasthen weighed out. The film coated beads were placed in a suitabletumbling type blender with the talc and blended for 15±5 minutes. Thebeads were then transferred to a suitable container(s) lined with twopolyethylene bags and the net weight was determined.

[0065] The so formed beadlets may then be filled in to capsules orshells, such as gelatin capsules for ease of swallowing.

[0066] The so formed enteric coated ddl product was found to gaveexcellent protection against gastric acid (at pH of 3) but had excellentrelease of ddl at pH's above 4.5.

We claim:
 1. An enteric coated pharmaceutical composition comprising a core in the form of a beadlet, pellet, granule or particle and an enteric coating for said core, said core comprising an acid labile medicament in an amount within the range from about 50 to about 100% by weight of said composition, a binder in an amount within the range from about 0 to about 10% by weight of said composition, a disintegrant in an amount within the range of from about 0 to about 10% by weight of said composition, and said enteric coating comprising a methacrylic acid copolymer, and a plasticizer said enteric coating imparting protection to said core so that said core is afforded protection in a low pH environment of 3 or less while capable of releasing medicament at a pH of 4.5 or higher, said pharmaceutical composition also comprising an anti-adherent in an amount within the range of from about 0.1 to about 4.0% by weight.
 2. The pharmaceutical composition according to claim 1 , wherein said core is in the form of a beadlet or pellet.
 3. The pharmaceutical composition according to claim 2 , wherein said core is in the form of a beadlet.
 4. The pharmaceutical composition according to claim 1 , wherein said enteric coating is present in a weight ratio to the core of within the range of from about 0.05:1 to about 0.6:1.
 5. The pharmaceutical composition according to claim 1 , wherein said enteric coating includes the methacrylic acid copolymer in an amount within the range of from about 5 to about 30% by weight, and said plasticizer in an amount within the range from about 0.5 to about 6% by weight, all of the above % being based on the solids content of said enteric coating.
 6. The pharmaceutical composition according to claim 5 , wherein said methacrylic acid copolymer is Eudragit L-30-D
 55. 7. The pharmaceutical composition according to claim 5 , wherein said plasticizer is diethyl phthalate, triethyl citrate, triacetin, tributyl sebecate, or polyethylene glycol.
 8. The pharmaceutical composition according to claim 7 , wherein said plasticizer is diethyl phthalate.
 9. The pharmaceutical composition according to claim 8 , wherein said enteric coating includes methacrylic acid copolymer and diethyl phthalate.
 10. The pharmaceutical composition according to claim 1 , wherein said anti adherent is a hydrophobic material.
 11. The pharmaceutical composition according to claim 10 , wherein the anti adherent is talc, magnesium stearate or fumed silica.
 12. The pharmaceutical composition according to claim 11 , wherein the anti-adherent is talc.
 13. The pharmaceutical composition according to claim 1 , wherein said anti-adherent is present in an amount within the range from about 0.1% to about 4.0% by weight, all of the above % being based on the solids content of said enteric coating.
 14. The pharmaceutical composition according to claim 1 , wherein the pH of said acidic enteric coating is adjusted using alkalizing agents to improve stability between said acid labile medicament in said core and said acidic enteric coating.
 15. The pharmaceutical composition according to claim 14 , wherein adjustment of the pH of said acidic enteric coating eliminates incompatibility between said acid labile medicament in said core and said acidic enteric coating.
 16. The pharmaceutical composition according to claim 15 , wherein adjustment of said pH of said acidic enteric coating eliminates the need for a protective subcoat between said acid labile medicament in said core and said acidic enteric coating.
 17. The pharmaceutical composition according to claim 16 , wherein elimination of said protective subcoat permits quicker release of said acid labile medicament in said core.
 18. The pharmaceutical composition according to claim 1 , wherein said medicament is present in an amount within the range of from about 50 to about 100% of the core composition when said core composition is uncoated.
 19. The pharmaceutical composition according to claim 1 , wherein said medicament is ddl.
 20. The pharmaceutical composition according to claim 1 , wherein said medicament is pravastatin, erythromycin, digoxin, pancreatin, ddA or ddC.
 21. The pharmaceutical composition according to claim 1 , wherein said core includes disintegrant present in an amount within the range of from about 0 to about 10.0% by weight.
 22. The pharmaceutical composition according to claim 1 , wherein said disintegrant is sodium starch glycolate, croscarmellose sodium, corn starch, or cross linked polyvinylpyrrolidone.
 23. The pharmaceutical composition according to claim 22 , wherein said disintegrant is sodium starch glycolate.
 24. The pharmaceutical composition according to claim 1 , wherein said core includes a binder present in an amount within the range of from 0 to about 10% by weight.
 25. The pharmaceutical composition according to claim 24 , wherein said binder is sodium carboxymethylcellulose, Avicel™ PH101, Avicel™ RC
 591. Avicel™ CL-611, Methocel™ E-5, Starch 1500, Hydroxypropyl Methylcellulose, Polyvinylpyrrolidone, Potassium Alginate or Sodium Alginate.
 26. The pharmaceutical composition according to claim 24 , wherein said binder is sodium carboxymethylcellulose.
 27. The pharmaceutical composition according to claim 24 , wherein said binder is alkaline in nature.
 28. The pharmaceutical composition according to claim 27 , wherein said said core comprising said acid labile medicament is made more stable by the inclusion of said alkaline binder.
 29. The pharmaceutical composition according to claim 1 , wherein said core comprising said acid labile medicament is made more stable by the inclusion of an alkaline ingredient such as magnesium oxide.
 30. The pharmaceutical composition according to claim 1 , having the following composition: Material % (range) CORE Drug (didanosine)   50-100.0 NaCMC   0-10.0 Na Starch Glycolate   0-10.0 COATING Eudragit L-30-D 55  5.0-30.0 Diethyl Phthalate 0.5-6.0 ANTI-ADHERENT COAT Talc 0.1-4.0


31. An enteric coated ddl comprising a core in the form of a beadlet or pellet which includes ddl in an amount within the range of from about 50 to about 100% by weight of said core, and an enteric coating which includes a methacrylic acid copolymer.
 32. ddl as defined to claim 31 , in the form of beadlets.
 33. ddl as defined in claim 32 , wherein the enteric coating includes a methacrylic acid copolymer and a plasticizer.
 34. ddl as defined in claim 33 , further comprising an anti-adherent.
 35. A process for the preparation of an enteric-coated pharmaceutical composition comprising the steps of: (a) preparing a dry blend comprising a medicament, a binder and a disintegrant, and setting a portion of said dry blend aside; (b) forming a wet mass from the remainder of said dry blend not set aside in step (a); (c) extruding said wet mass to form an extrudate and spheronizing said extrudate into high-potency beadlets by dusting said wet mass extrudate with said portion of said dry blend set aside in step (a); (d) coating said beadlets with an enteric coating polymer and plasticizer in an aqueous media; and (e) blending said coated beadlets with an anti-adherent.
 36. The process according to claim 35 , further comprising the step of separating said spheronized high potency beadlets formed in step (c) using a #10 and a #18 size mesh screen to form 10/18 mesh product fraction sized beadlets prior to said coating step (d).
 37. The process according to claim 35 , wherein said medicament is an acid labile drug.
 38. The process according to claim 37 , wherein said acid labile drug is selected from the group consisting of ddl, pravastatin, erythromycin, digoxin, pancreatin, ddA or ddC.
 39. The process according to claim 38 , wherein said medicament is ddl.
 40. The process according to claim 35 , wherein said binder is sodium carboxymethylcellulose.
 41. The process according to claim 35 , wherein said disintegrant is sodium starch glycolate.
 42. The process according to claim 35 , wherein the wet mass is formed by the addition of a granulation solvent.
 43. The process according to claim 42 , wherein said granulation solvent is water.
 44. The process according to claim 35 , wherein said plasticizer is diethyl phthalate.
 45. The process according to claim 44 , wherein said enteric coating includes methacrylic acid copolymer and diethyl phthalate.
 46. The process according to claim 45 , wherein said methacrylic acid polymer is Eudragit L-30-D
 55. 47. The process according to claim 35 , wherein said anti-adherent is talc.
 48. The process according to claim 35 , further providing the step of filling said coated beadlets prepared in (e) into a dissolvable capsule. 